The Ryanodine Receptor Calcium Channel of β-Cells

Abstract

The list of Ca²⁺ channels involved in stimulus-secretion coupling in β-cells is increasing. In this respect the roles of the voltage-gated Ca²⁺ channels and IP₃ receptors are well accepted. There is a lack of consensus about the significance of a third group of Ca²⁺ channels called ryanodine (RY) receptors. These are large conduits located on Ca²⁺ storage organelle. Ca²⁺ gates these channels in a concentration- and time-dependent manner. Activation of these channels by Ca²⁺ leads to fast release of Ca²⁺ from the stores, a process called Ca²⁺-induced Ca²⁺ release (CICR). A substantial body of evidence confirms that β-cells have RY receptors. CICR by RY receptors amplifies Ca²⁺ signals. Some properties of RY receptors ensure that this amplification process is engaged in a context-dependent manner. Several endogenous molecules and processes that modulate RY receptors determine the appropriate context. Among these are several glycolytic intermediates, long-chain acyl CoA, ATP, cAMP, cADPR, NO, and high luminal Ca²⁺ concentration, and all of these have been shown to sensitize RY receptors to the trigger action of Ca²⁺. RY receptors, thus, detect co-incident signals and integrate them. These Ca²⁺ channels are targets for the action of cAMP-linked incretin hormones that stimulate glucose-dependent insulin secretion. In β-cells some RY receptors are located on the secretory vesicles. Thus, despite their low abundance, RY receptors are emerging as distinct players in β-cell function by virtue of their large conductance, strategic locations, and their ability to amplify Ca²⁺ signals in a context-dependent manner.